A murine model has been developed of graft-versus-host disease (GVHD) due to minor histocompatibility antigens (minor HA) in two strain combinations selected for H-2 identity and for mutual nonreactivity in MLC: C57BL/6-LP (H-2bcombination) and B10.D2/nSn-BALB/c (H-2dcombination). This model possesses many characteristics in common with human GVHD, including acute and chronic forms and has been used to systematically study the immune mechanisms that produce GVHD in response to minor HA. A new assay of the proliferative response to minor HA has been developed to study the role of non-CTL in the pathogenesis of minor HA-GVHD. Congenic strains of mice developed between C57BL/10, LP, and 129 mice have been used to demonstrate that multiple minor H antigenic differences must exist between donor and recipient strains for GVH to develop. Studies are in progress to evaluate the immunoregulation of cellular responses to minor HA in mice with transplants. Attempts to study the proliferative response of spleen cells from mice with GVHD to recipient strain and third party antigens led to the demonstration that these spleen cells were unable to respond to foreign antigens in mixed lymphocyte culture. Further studies demonstrated that mice with minor antigen GVHD have an acquired form of severe combined immunodeficiency and are unable to develop either cell-mediated or humoral immunity to specific antigens. The specific mechanism of this immunodeficiency is under investigation using both in vivo and in vitro techniques. Using adoptive transfer methods, we have been able to transfer minor antigen GVHD to secondary recipients. The cells that transfer GVHD are Thy-1+ and Lyt-2+. The ceIls that initiate GVHD have been further defined: the Lyt phenotype varies with the specific strain combination tested. (LB)